Mesenchymal stromal cells (MSCs) have the capacity for self-renewal and multi-lineage differentiation, have many advantages over other cells, and are thought to be one of the most promising cell sources for cell-based treatments. In fact, MSCs have already been widely applied in clinics as a treatment for numerous disorders, including orthopedic diseases, such as bone fracture, articular cartilage injury, osteoarthritis (OA), femoral head necrosis, degenerative disc, meniscus injury, osteogenesis imperfecta (OI), and other systemic bone diseases. With the progressions in R&D, the safety and efficacy of MSC-based treatments in orthopedic diseases have been largely recognized, but many challenges still exist. In this chapter, we intend to briefly update the recent progressions and discuss the potential issues in the target areas. Hopefully, our discussion would be helpful not only for the clinicians and the researchers in the specific disciplines but also for the general audiences.